Synthesis of chiral sulfoximines derived from 3-aminoquinazolinones and their catalysis of enantioselective diethylzinc addition to aldehydes

Article abstract of DOI:10.1039/c1ob06205k

A series of sulfoxides were sulfoximinated using oxidative addition of 3-aminoquinazolinones by lead tetraacetate in the presence of hexamethyldisilazane. They were applied for the first time in catalytic enantioselective addition to aromatic aldehydes with a product enantiopurity (ee) of 92% in the case of 2-methoxybenzaldehyde.

Full text of DOI:10.1039/c1ob06205k

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PAPER
Synthesis of chiral sulfoximines derived from 3-aminoquinazolinones and their
catalysis of enantioselective diethylzinc addition to aldehydes†
Semistan Karabuga,a Murat Cakici,b Cavit Kazaz,b Ertan Sahin,b Hamdullah Kilicb and Sabri Ulukanli*c
Received 19th July 2011, Accepted 30th August 2011
DOI: 10.1039/c1ob06205k
A series of sulfoxides were sulfoximinated using oxidative addition of 3-aminoquinazolinones by lead
tetraacetate in the presence of hexamethyldisilazane. They were applied for the first time in catalytic
enantioselective addition to aromatic aldehydes with a product enantiopurity (ee) of 92% in the case of
2-methoxybenzaldehyde.
of the hydroxyl group and the oxygen of quinazolinone carbonyl
group as in 8.
Sulfoximines are of considerable interest since they are sub-
strates for conversion into biologically active molecules such as
1. Introduction
Oxidation of the family of N-aminoheterocycles 1–5, with
lead tetraacetate (LTA) in the presence of electron-rich and
alkaloids13–19 and amino acids.20–23 Their chirality makes them
potentially useful in stereoselective synthesis24–29 and new synthetic
applications are currently being developed.20,27,30–36; of particular
interest is their bioactivity as tumour metastasis inhibitors.37–39
This growing interest is also focussed on their significant poten-
tial in asymmetric synthesis24–29 and new synthetic applications
are currently being developed.20,27,30–36 Bolm and Okamura have
studied the catalytic applications of a new class of sulfoximine
ligands and their N-acylated derivatives.30,31,40 A synthetically
valuable NH-sulfoximines procedure has been developed by
Yudin by electrochemical sulfoximination of sulfoxide using N-
aminophthalimide followed by cleavage of the N–N bond.41
In 1996, Bolm’s group introduced sulfoximine as an enantiopure
ligand in a Pd complex-catalyzed asymmetric allylation reaction,
yielding the product with 73% ee.42 Subsequently, Bolm and
others43 developed a series of enantiopure sulfoximines 10–13
(Scheme 3) for use in Diels–Alder,28,44 carbonyl-ene,45,46 asym-
metric hydrogenation,27,47 Mukaiyama aldol,26,48,49 and trimetylsi-
lylcyanation of aldehyde50 reactions as well as enantioselective
conjugate addition of diethylzinc to chalcones.51
electron-deficient alkenes results in aziridines, often in excellent
yields1 (Scheme 1). Among these N-aminoheterocycles 1–5, 3-
aminoquinazolinones 1 (QNH2) have been the most extensively
used.
Scheme 1
Quinazolinones and quinazolines are also present in naturally
occurring alkaloids and play a crucial role in biological activity.2–5
Reagent6–10 or substrate-controlled11 diastereoselective aziridina-
tion of alkenes can be accomplished by incorporation of a chiral
centre into the 2-position of quinazolinone 1 or into the alkene.
We have recently reported12 that aziridination of allylic alcohols
6 using 2-ethyl-3-acetoxyaminoquinazolinone 7 (Q1NHOAc) as
the aziridinating agent, gives aziridine diastereoselectivities of
up to >99 : 1 (Scheme 2). This high syn-diastereoselectivity was
presumed to result from hydrogen bonding between the hydrogen
In this paper we describe, in detail, the imination of sulfoxides
using 3-aminoquinazolinones and their catalysis of (enantioselec-
tive) diethylzinc addition to aldehydes.
2. Results and Discussions
aDepartment of Chemistry, Faculty of Science and Letters, Kahramanmaras
Sutcu Imam University, 46100, Kahramanmaras, Turkey
We recently communicated that in sulfoximination of sulfoxide
using Q1NHOAc 7, yields are improved by the presence of
hexamethyldisilazane (HMDS)52 (Scheme 4). Initially, DMSO was
bDepartment of Chemistry, Faculty of Science, Ataturk University, 25240,
Erzurum, Turkey
cDepartment of Chemistry, Faculty of Science and Letters, Osmaniye
Korkut Ata University, Karacaoglan Campus, 80000, Osmaniye, Turkey.
E-mail: sabriulukanli@osmaniye.edu.tr; Fax: 0090 3288251030; Tel: 0090
3288271000
◦
converted into sulfoximine at -18 C in only 35% yield using an
equimolar molar of Q1NHOAc 7, as well as QH 6 which is a
by-product in the aziridination of electron-deficient alkenes.11,53
In this sulfoximination, competitive decomposition of
Q1NHOAc 7 (stable at <0 ◦C) is a consequence of the acetic acid
(AcOH) produced in the acetoxylation of 3-aminoquinazolinone
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra, HPLC data and crystal structure determination. CCDC reference
number 818097. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1ob06205k
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Scheme 2
reaction indicated a predominance of the (R)-sulfoxide by HPLC
analysis using chiral column (Chiralcel OD-H). Hence the absolute
configuration of the major sulfoximine (20a) diastereoisomer is
S as displayed in Scheme 6. As was previously known, reagent-
controlled diastereoselective aziridination of styrene with (S)-
tert-leucine derived 3-aminoquinazolinone 30 (Q3NH2) gave a
1 : 1.5 ratio of aziridine diastereoisomers. However, when this
aziridination was repeated in the presence of Ti(OPri)4, this
ratio of aziridines is >50 : 1. The same enhanced diastereose-
lectivities were also obtained for butadiene and indene derived
aziridines.54,55
Scheme 3
Repetition of our sulfoximination reaction using Ti(OPri)4
present, however gave no enhancement of diastereoselectivity (d.r.
1 : 1) from comparison of the same signals previously compared
in the 1H NMR spectrum of the sulfoximine. Separation of minor
20a (Rf 0.2) and major (Rf 0.12) sulfoximine 20b diastereoisomers
as colourless oils was accomplished by chromatography over silica.
Alkyl phenyl sulfoxides 16b–h were then iminated under the same
reaction conditions and the diastereoisomer ratios of the resulting
sulfoximines measured by NMR but in every case a 1 : 1 ratio was
obtained.
Each of the crude diastereoisomeric sulfoximines was then
chromatographed over silica and separated as single oily or solid
diastereoisomers except 22 and 25. Enrichment of the phenyl-
cyclohexylsulfoximine 25 to a 95 : 5 ratio of diastereoisomers
was achieved by crystallisation from ethanol. A single crystal
of sulfoximine diastereoisomer 23a suitable for X-ray crystal
structure determination was also prepared by crystallisation from
ethanol. The compound 23a crystallizes in the monoclinic non-
centrosymmetric chiral space group P21 with four molecules in
the unit cell. It has the configuration shown in Fig. 1, which is the
(S)-configuration at the chiral center (related to the asymmetric C
atom at C19 and C19¢) and related R-chiral sulfoxides was assigned
[Flack parameter x: -0.012(0.06)].
Absolute configuration of N-phthalimidosulfoximines and re-
lated (S)-chiral sulfoxides has previously been assigned by exciton-
coupled circular dichroism.56 Sulfoximines prepared from N-
aminophthalimide and sulfoxides are believed to be formed with
retention of configuration at sulfur.
We prepared enantiopure (S)-t-butyl phenyl sulfoxide 23 by
the procedure of Kagan57 and iminated using Q2NHOAc 19 to
give sulfoximine 23b. The configuration at sulfur was retained
in the sulfoximine product which is in agreement with the
known configuration of the authentic samples as has been shown
previously. The mechanism shown in Fig. 2 for Q2NHOAc 19
imination of sulfoxides is analogous to the Bartlett mechanism for
Scheme 4
1 (R = Et) and in the sulfoximination steps. Using HMDS (2 eq)
to scavenge AcOH, increasing to 2 eq the ratio of DMSO (2 eq)
and lowering the reaction temperature to -70 ◦C then finishing the
reaction at -10 ◦C gave the product 14 as crystalline solid in 95%
yield (see General procedure in Experimental section). A number
of alkyl phenyl sulfoxides were then iminated (Scheme 5) with is
modified procedure described above using Q1NHOAc 7 and giving
the sulfoximines shown up to 70% isolated yields.
Scheme 5
The advantage of using 3-aminoquinazolinones 1 over N-
aminoheterocycles 2–5 in aziridination of alkenes is the ease of
incorporation of a chiral centre into its 2-position, which makes
available aziridines in enantiopure form.1 For this reason, and as
part of our program devoted to the study of this new sulfoximina-
tion process, we were keen on devising a diastereoselective version
of this reaction.
Thus, imination of methyl phenyl sulfoxide 16a with 19 gave
the product 20 in 66% yield (Scheme 6). An NMR spectrum
of the crude product showed a 1.3 : 1 ratio of sulfoximine
diastereoisomers (20a and 20b) from comparison of methyl signal
intensity at the sulfur chiral centre at d 3.36 and 3.32 ppm
respectively. Unreacted methyl phenyl sulfoxide 16a from this
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Scheme 6
Scheme 7
Examination of Table 1 shows the formation of enantiomerically
enriched product 1-phenyl-1-propanol 29 in the presence of
sulfoximine catalysts 23b, and 26 in 62% and 61% ee respectively
and in excellent yields (99%). The reaction when carried out using
diastereomeric mixture (1 : 1) of sulfoximine 22 or of sulfoximine
25 (19 : 1), displayed almost the same enantioselection (58% and
57% ees).
Fig. 1 An ORTEP drawing of the molecule 23a. The asymmetric unit
contains two independent molecules with nearly identical geometries.
Displacement ellipsoids are drawn at the 40% probability level.
Different and better differentiated substituents on the chiral
centre on the 2-position of the quinazolinones could give better di-
astereoselectivities for imination of sulfoxides and enantioselectiv-
ities in catalytic C–C bond formations. For this reason, we repeated
the imination process of t-butyl phenyl sulfoxide and diphenyl
sulfoxide using 3-aminoquinazolinones 30–3255,58 (Scheme 8). In
each case, t-butyl phenyl sulfoxide derived sulfoximines 36 and 37
contained 1 : 1 diastereoisomeric mixtures from analysis of their 1H
NMR spectra. Repetition of the catalytic enantioselective reaction
as in Scheme 7 reveals slightly higher enantioselectivities using
(S)-valin derived quinazolinone sulfoximine ligands 34 and 37b
(68% ee Table 2, Entries 2 and 7). There was no observation of
enantioselection in formation of the corresponding alcohol, when
mandelic acid derived quinazolinone sulfoximine 35 was used as
ligand (Entry 3). Because of its easy preparation and purification,
ligand 34 was used in subsequent variations of reaction conditions
including the influence of the Lewis acid Ti(OPri)4, solvent,
temperature as well as ligand percentage.
Changing the reaction condition in presence of Ti(OPri)4 (Entry
8) gave a lower ee. When the temperature was lowered to -20 ◦C
(Entry 9), the reaction proceeded with good yield and with an
ee somewhat higher than at 0 ◦C. The lowest enantioselectivity
(18% ee) and product yield (3%) was achieved in the presence of
THF as solvent. When the reaction was performed in Et2O and
the reaction temperature lowered to -40 ◦C, we obtained the best
enantioselection (90% ee Entry 15). Increasing the temperature
to ambient had adverse effects on the enantioselectivity (21% ee)
(Entry 16). Decreasing to temperature to -70 ◦C gave a good
enantioselectivity (89% ee) but the lowest product yield (21%)
(Entry 17). Altering the mol equivalent of Et2Zn (Entry 18 and
19) or of sulfoximine (Entry 20 and 21) gave no improvements in
enantioselectivity.
Fig. 2
mCPBA epoxidation of alkenes or for aziridination of electron
rich alkenes e.g. styrene by Q2NHOAc 19.1,7
To examine the performance of sulfoximines 20–27 as chiral
ligands in catalytic enantioselective addition of alkylzinc reagents
to aldehydes, we chose the addition of Et2Zn to benzaldehyde 28
as a reference reaction (Scheme 7). The reaction was attempted at
the temperature of 0 ◦C, 10% ligand, 2 eq of Et2Zn and toluene as
solvent and the results are shown in Table 1.
Table 1 Addition of diethylzinc to benzaldehyde in the presence of ligand
20–27
Entry
Sulfoximine
ee (%)
Yield (%)
Configuration
1
20a S,SS
20b S,RS
21a
21b
22
42
50
31
47
58
45
62
36
44
57
61
24
56
94
81
94
53
99
99
89
91
53
99
85
S
S
S
S
S
S
S
S
S
S
S
S
2
3
4
5
6
23a S,RS
23b S,SS
24a
7
8
9
24b
10
11
12
25
26
27
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Table 2 Et2Zn addition benzaldehyde catalysed by 33–37
Entry
Sulfoximine
Lewis acid
Temp. ◦
C
Solvent
Ee (%)
Yield (%)
Configuration
1
33
—
—
—
—
—
—
—
Ti(OPi)4
Ti(OPi)4
Ti(OPi)4
Ti(OPi)4
Ti(OPi)4
Ti(OPi)4
Ti(OPi)4
Ti(OPi)4
Ti(OPi)4
Ti(OPi)4
Ti(OPi)4
Ti(OPi)4
Ti(OPi)4
Ti(OPi)4
0
0
0
0
0
0
0
0
-20
-20
-20
-20
-20
-20
-40
rt
-70
-40
-40
-40
-40
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Hexane
Et2O
46
68
0
99
97
99
98
98
96
72
94
92
99
83
3
57
85
67
98
11
70
52
64
63
S
S
S
R
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
2
34
3
35
4
36a
36b
37a
37b
34
44
48
50
68
51
77
76
80
18
61
72
90
21
89
80
90
77
91
5
6
7
8
9
34
10
11
12
13
14
15
16
17
18
19
20
21
34
34
34
THF
34
CH2Cl2
Dioxane
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
34
34
34
34
34a
34b
34c
34d
a 3 eq Et2Zn; b 1.5 eq Et2Zn; c 5% ligand used; d 20% ligand used;
Scheme 8 Synthesis of ligands 33–37.
We then examined a number of aromatic aldehydes. The
electron-poor ortho-, meta- and p-chlorobenzaldehydes and
the electron-rich methoxybenzaldehydes gave enantioselectivities
ranging between 81 and 92% ee and moderate to good yields of
alcohols, except 4-methoxybenzaldehyde; 1-naphthaldehyde gave
only 17% yield and 60% ee. Methyl substituted benzaldehydes
produced moderate yields of alcohols and very good enantios-
election (88% and 89% ees). As can be seen from the Table
3, the best ee and yield of alcohol was accomplished using 2-
methoxybenzaldehyde.
Table 3 Et2Zn addition aromatic aldehydes 28, 38–47 using ligand 34
Aldehyde
eea (%)
Yieldb (%)
Configurationc
benzaldehyde 28
90
81
89
85
92
87
58
89
88
60
5
67
42
54
50
73
28
5
55
63
17
99
S
2-chlorobenzaldehyde 38
3-chlorobenzaldehyde 39
4-chlorobenzaldehyde 40
2-methoxybenzaldehyde 41
3-methoxybenzaldehyde 42
4-methoxybenzaldehyde 43
3-methylbenzaldehyde 44
4-methylbenzaldehyde 45
1-naphthaldehyde 46
S
—
S
3. Conclusion
S
In summary, we have described in detail a synthetically valuable
way of making sulfoximines and evaluation of their catalytic
enantioselective effect in Et2Zn addition to aldehydes in the
absence and presence of Ti(OPri)4. It is noteworthy that the
preferred sulfoximine 34 was easily synthesised in five steps in
an overall yield (41%) without the need for chromatography. In
general, the best results are obtained with benzaldehyde and 2-
methoxybenzaldehyde with enantioselectivities 90% ee and 92%
ee respectively.
S
S
S
S
S
2-pyridinecarboxaldehyde 47
—
a Determined by GC using a b-dex (30 m ¥ 0.25 mm ¥ 0.25 mm) column.
b Isolated yields. c Assigned by comparison of the chromatogram with those
reported in the literature.59–62
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(CDCl3, 400 MHz): d 1.24 (3H, t, J 7.3 Hz, CH2CH3), 2.97 (2H,
q, J 7.3 Hz, CH2CH3), 3.22 (6H, s, CH3SCH3), 7.25 to 7.59 (3H,
m, 6-H, 7-H, 8-H (Q)) and 8.09 (1H, ddd, J 8.1 Hz and 2.2 and
1.4 Hz, 5-H (Q)). 13C NMR (CDCl3, 100 MHz): d 10.8, 28.1,
42.7, 121.2, 126.1, 126.6, 127.2, 134.1, 146.7, 161.3 and 161.9).
Elemental analysis calculated for C12H15N3O2S: C, 54.32, H, 5.70,
N, 15.84, O, 12.06, S, 12.08%. Found: C, 54.35, H, 5.91, N, 15.95,
S, 11.85%.
4. Experimental
Melting points (◦C) were obtained in an Electrothermal 9100
apparatus and are uncorrected. H and 13C NMR spectra were
1
performed on a Varian Mercury spectrometer at 400 and 100 MHz
in CDCl3 with tetramethylsilane as an internal standard and
signals are evaluated using MestreC computer software. Elemental
analysis was recorded on a LECO CHNS 932 elemental analyzer
and IR spectra of all compounds were performed using Perkin
Elmer spectrometer. Mass spectra were recorded on a Kratos
Concept 1H Magnetic Sector Mass Spectrometer at Leicester
University. Optical rotations of enantio–enriched compounds
were recorded on a Labart WZZ-2A and Berlingham Bentley
ADP220 at 589 nm using sodium D line wavelength light at
room temperature with a path length of 10 cm. Concentrations
are quoted in gdm-3 and values given have units of g-1L-1¥102.
Enantiomeric excesses of alcohols were determined using a
Hewlett-Packard 6850 gas chromatograph with a Supelco b-
DEXTM column (30 m ¥ 0.25 mm ¥ 0.25 mm). Enantiomeric purity
of ligands was determined by chiral HPLC (Hawlett Pachard 1200)
analysis using a enantiopure stationary phase (Daicel Chiralcel
OD-H), eluting with i-PrOH-hexane, and using UV detection
at 254 nm. All crude products were examined by Thin Layer
Chromatography (TLC) prior to purification. TLC was performed
on silica gel 60 F254 on aluminium sheets with a 0.2 mm layer
manufactured by Merck & Co and the visualising agent was UV
fluorescence (254 nm). The Chromatotron (Harrison Research
California) used for purification was model 7024T with circular
Kieselgel 60 PF254 silica plates. Silica gel (230–400 mesh, supplied
by Fluka) chromatographic purification was performed using
silica packed glass columns (various sizes). The amount of silica
used was approximately 40–60 times by weight relative to material
applied to the column. The eluting solvents (hexane:ethyl acetate
mixture in all cases), were reagent grade and used as received. Low
temperature experiments (-70 ◦C) were carried out using HAAKE
90 cryostat for controlling the reaction bath temperature.
Sulfoximination of phenyl methyl sulfoxide using Q1NH2
General procedure 1 was followed using Q1NH2 1 (0.3 g,
1.58 mmol), LTA (0.77 g, 1.75 mmol), HMDS (0.51 g, 3.17 mmol)
and phenyl methyl sulfoxide 16a (0.44 g, 3.17 mmol) in a solution
in dichloromethane (6 cm3). The crude product crystallised on
addition of ethanol to give sulfoximine 17a as a colourless solid
(0.3 g, 57%) mp 145–147 ◦C (from ethanol) IR (in CH2Cl2 solution)
n
max/ cm-1: 3586 w, 3064 w, 2974 w, 2934 w 1672 s, 1591 s and 1568
w. 1H NMR (CDCl3, 400 MHz): d 1.35 (3H, t, J 7.3 Hz, CH2CH3),
3.17 (2H, m, CH2CH3), 3.31 (3H, s, PhSCH3), 7.39 to 7.75 (6H, m,
6-H, 7-H, 8-H (Q) and 3H (Ph)), 8.21 (1H, dd, J 8.2 Hz and 1.1 Hz,
5-H (Q)) and 8.33 (2H, dd, 8.4 Hz and 1.7 Hz, 2H (Ph)). 13C NMR
(CDCl3, 100 MHz): d 10.8, 28.2, 43.8, 121.3, 126.2, 127.3, 128.8,
129.6, 134.1, 137.3, 146.8, 161.5 and 161.8). Elemental analysis
calculated for C17H17N3O2S: C, 62.36, H, 5.23, N, 12.83, O, 9.77,
S, 9.79%. Found: C, 62.13, H, 5.35, N, 12.97, S, 9.87%.
Sulfoximination of phenyl ethyl sulfoxide using Q1NH2
General procedure 1 was followed using Q1NH2 1 (0.2 g,
1.1 mmol), LTA (0.52 g, 1.16 mmol), HMDS (0.34 g, 2.12 mmol)
and phenyl ethyl sulfoxide 16b (0.33 g, 2.12 mmol) in a solution
in dichloromethane (6 cm3). The crude product crystallised on
addition of ethanol to give sulfoximine 17b as a colourless solid
(0.22 g, 61%) mp 155–157 ◦C (from ethanol) IR (in CH2Cl2
solution) nmax/ cm-1: 3494 w, 3065 w, 2978 w, 2937 w, 2875 w
1675 s, 1592 w and 1568 w. 1H NMR (CDCl3, 400 MHz): d 1.21
(3H, t, J 7.6 Hz, SCH2CH3), 1.34 (3H, t, J 7.3 Hz, QCH2CH3), 3.2
(2H, m, QCH2CH3), 3.51 (3H, m, SCH2CH3), 7.25 to 7.72 (6H,
m, 6-H, 7-H, 8-H (Q) and 3H (Ph)), 8.17 (1H, ddd, J 8.4, 2.2 and
0.7 Hz, 5-H (Q)) and 8.24 (2H, ddd, 8.4, 6.9 and 1.4 Hz, 2H (Ph)).
13C NMR (CDCl3, 100 MHz): d 8.2, 10.9, 28.3, 50.1, 121.2, 126.1,
126.8, 127.2, 129.4, 129.5, 134.0, 134.2, 135.5, 146.8, 161.5 and
162.0). Elemental analysis calculated for C18H19N3O2S: C, 63.32,
H, 5.61, N, 12.31, O, 9.37, S, 9.39%. Found: C, 63.37, H, 5.68, N,
12.43, S, 9.36%.
General procedure 1 for sulfoximination using
2-ethyl-3-aminoquinazolinone 1
3-Amino-2-ethyl-quinazolinone Q1NH2 1 (0.3 g, 1.58 mmol) and
acetic acid-free lead tetraacetate (LTA) (0.77 g, 1.75 mmol) were
added alternately and continuously in very small portions over
15 min. to a vigorously stirred solution of dry dichloromethane
(6 cm3) at -40 ◦C. The mixture was then stirred for a further
5 min. to give a solution of the 3-acetoxyaminoquinazolinone.
The temperature was lowered to -70 ◦C, before dropwise addition
of dimethyl sulfoxide (0.25 g, 3.17 mmol) as a solution in
dichloromethane (3 cm3) containing HMDS (0.51 g, 3.17 mmol)
and then the temperature of the solution allowed to rise to
-10 ◦C (~1.5 to 2 h) with continuous stirring. Saturated aqueous
sodium hydrogen carbonate (30 cm3) was added and the mixture
extracted with dichloromethane (3 ¥ 30 cm3). The organic layer
was separated, washed with water (3 ¥ 30 cm3), dried with sodium
sulfate and the solvent removed by evaporation under reduced
pressure. The crude product crystallised on addition of ethanol
to give sulfoximine 14 as a colourless solid (0.4 g, 95%) mp 130–
132 ◦C (from ethanol) IR (in CH2Cl2 solution) nmax/ cm-1: 3479
Sulfoximination of phenyl isopropyl sulfoxide using Q1NH2
General procedure 1 was followed using Q1NH2 1 (0.2 g,
1.1 mmol), LTA (0.52 g, 1.16 mmol), HMDS (0.34 g, 2.12 mmol)
and phenyl isopropyl sulfoxide 16c (0.36 g, 2.12 mmol) in a solu-
tion in dichloromethane (6 cm3). The crude product crystallised
on addition of ethanol to give sulfoximine 17c as a colourless
solid (0.23 g, 61%) mp 119–121 ◦C (from ethanol) IR (in CH2Cl2
solution) nmax/ cm-1: 3064 w, 2978 w, 2936 w, 2873 w, 1678 s, 1591
s and 1568 w. 1H NMR (CDCl3, 400 MHz): d 1.22 (3H, d, J 6.9
Hz, CH3CHCH3), 1.35 (3H, t, J 7.3 Hz, QCH2CH3), 1.48 (3H,
d, J 6.9 Hz, CH3CHCH3), 3.16 (2H, m, QCH2CH3), 3.87 (1H,
m, CH3CHCH3), 7.27 to 7.76 (6H, m, 6-H, 7-H, 8-H (Q) and 3H
1
w, 3011 w, 2929 w 1672 s, 1608 w, 1591 s and 1568 w. H NMR
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(Ph)), 8.25 (3H, m, 5-H (Q)) and 2H (Ph)). 13C NMR (CDCl3,
100 MHz): d 11.0, 16.1, 17.3, 28.6, 29.3, 57.5, 121.2, 125.9, 126.7,
127.0, 129.4, 129.1, 129.7, 133.7, 133.8, 146.6, 161.4 and 161.5).
Elemental analysis calculated for C19H21N3O2S: C, 64.20, H, 5.95,
N, 11.82, O, 9.00, S, 9.02%. Found: C, 64.24, H, 6.09, N, 11.92, S,
8.82%.
(Q)). 13C NMR (CDCl3, 100 MHz): d 11.1, 25.2, 25.52, 25.56,
25.89, 26.6, 28.6, 64.7, 121.3, 125.8, 126.8, 126.9, 129.0, 129.8,
133.6, 133.7, 136.1, 146.6, 161.5 and 162.6). Elemental analysis
calculated for C22H25N3O2S: C, 66.81, H, 6.37, N, 10.62, O, 8.09,
S, 8.11%. Found: C, 66.46, H, 6.45, N, 10.78, S, 8.18%.
Sulfoximination of dimethyl sulfoxide using Q2NH2
Sulfoximination of phenyl tert-butyl sulfoxide using Q1NH2
General procedure 1 was followed using Q2NH2 18 (0.3 g,
1.46 mmol), LTA (0.71 g, 1.61 mmol), HMDS (0.34 g,
2.12 mmol) and DMSO 16h (0.23 g, 2.93 mmol) in a solution
in dichloromethane (5 cm3). The crude product was then chro-
matographed over silica and eluting with hexane–ethyl acetate 1 : 1
gave sulfoximine 27 (Rf 0.23) as a colourless oil (0.26 g, 64%). [a]D =
+46.7 (c = 0.87, CHCl3), (Found: MH+ 282.0908. C12H17N3O3S
requires M 282.0912), IR (in CH2Cl2 solution) nmax/ cm-1: 3450 m,
General procedure 1 was followed using Q1NH2 1 (0.15 g,
0.8 mmol), LTA (0.38 g, 0.87 mmol), HMDS (0.25 g, 1.58 mmol)
and phenyl tert-butyl sulfoxide 16d (0.25 g, 1.38 mmol) in a solu-
tion in dichloromethane (6 cm3). The crude product crystallised
on addition of ethanol to give sulfoximine 17d as a colourless
solid (0.18 g, 60%) mp 127–128 ◦C (from ethanol) IR (in CH2Cl2
solution) nmax/ cm-1: 3065 w, 2977 w, 2934 w 1679 s, 1591 s and
1
1568 w. H NMR (CDCl3, 400 MHz): d 1.38 (3H, t, J 7.3 Hz,
1
QCH2CH3), 1.53 (9H, s, tBu), 3.10–3.36 (2H, m, QCH2CH3), 7.24
to 7.69 (6H, m, 6-H, 7-H, 8-H (Q) and 3H (Ph)), 8.03 (1H, dd,
J 7.69 and 1.1 Hz, 5-H (Q)) and 8.10 (2H, dd, 8.7, and 1.4 Hz,
2H (Ph)). 13C NMR (CDCl3, 100 MHz): d 11.2, 24.6, 28.8, 63.7,
121.3, 125.7, 126.7, 126.8, 128.6, 131.4, 133.6, 134.9, 135.1, 146.4,
161.2 and 161.5). Elemental analysis calculated for C20H23N3O2S:
C, 65.01, H, 6.27, N, 11.37, O, 8.66, S, 8.68%. Found: C, 65.04, H,
6.22, N, 11.50, S, 8.51%.
3055 w, 2960 w, 2895 m, 2840 w, 1684 s, 1605 s and 1572 w. H-
NMR (CDCl3, 400 MHz): d 1.57 (3H, d, J 6.4 Hz, CHOHCH3),
3.34 (3H, s, CH3SCH3), 3.35 (3H, s, CH3SCH3), 4.36 (1H, d, J 6.4
Hz, CHOHCH3), 5.27 (1H, m, CHOHCH3), 7.47 (1H, t, J 7.3,
7-H, (Q)), 7.70–7.77 (2H, m, 6-H, 8-H (Q)) and 8.24 (1H, dd, J 1.1
Hz and 8.06 Hz, 5-H (Q)). 13C-NMR (CDCl3, 100 MHz): d 17.7,
21.5, 42.2, 42.6, 44.0, 44.2, 65.6, 68.1, 121.4, 121.8, 126.7, 126.8,
126.9, 127.1, 127.3, 127.9, 134.2, 134.4, 145.9, 146.3, 156.7, 161.1,
161.9, 170.8,
Sulfoximination of phenyl benzyl sulfoxide using Q1NH2
General procedure 1 was followed using Q1NH2 1 (0.2 g,
1.1 mmol), LTA (0.52 g, 1.16 mmol), HMDS (0.34 g, 2.12 mmol)
and phenyl benzyl sulfoxide 16e (0.46 g, 2.12 mmol) in a solution
in dichloromethane (6 cm3). The crude product crystallised on
addition of ethanol to give sulfoximine 17e as a colourless solid
(0.25 g, 62%) mp 136–138 ◦C (from ethanol) IR (in CH2Cl2
solution) nmax/ cm-1: 3064 w, 2936 w, 2858 w, 1678 s, 1608 w, 1591
Sulfoximination of phenyl methyl sulfoxide using Q2NH2
General procedure 1 was followed using Q2NH2 18 (0.2 g,
0.97 mmol), LTA (0.47 g, 1.07 mmol), HMDS (0.31 g, 1.94 mmol)
and phenyl methyl sulfoxide 16a (0.27 g, 1.95 mmol) in a solution
in dichloromethane (6 cm3) to give sulfoximine 20 as a colorless
oil. The crude product contained a 1.3 : 1 ratio of sulfoximine
diastereoisomers from comparison of signals at d 3.36 and 3.32
in its NMR spectrum (see below). The crude product was then
chromatographed over silica and eluting with hexane–ethyl acetate
2 : 1 gave minor sulfoximine 20a diastereoisomer (Rf 0.2) as a
colourless oil (0.1 g, 29%).
1
s and 1568 w. H NMR (CDCl3, 400 MHz): d 1.31 (3H, t, J 7.3
Hz, QCH2CH3), 3.11 (2H, m, QCH2CH3), 4.71 (2H, s, PhCH2),
6.93 (2H, dd, J 6.9 and 1.4 Hz, 2H (Ph)), 7.12 to 7.72 (9H, m, 6-H,
7-H, 8-H (Q) and 6H (Ph)), 7.99 (2H, ddd, 8.4, 2.9 and 1.8 Hz, 2H
(Ph)) and 8.22 (1H, ddd, J 8.4, 7.3 and 0.7 Hz, 5-H (Q)). 13C NMR
(CDCl3, 100 MHz): d 10.9, 28.2, 62.6, 121.3, 126.2, 126.8, 127.3,
128.0, 128.6, 129.0, 129.2, 129.6, 131.2, 134.1, 134.2, 135.0, 146.8,
161.6 and 162.2). Elemental analysis calculated for C23H21N3O2S:
C, 68.46, H, 5.25, N, 10.41, O, 7.93, S, 7.95%. Found: C, 68.26, H,
5.28, N, 10.50, S, 7.94%.
[a]D -49.2 (c 0.5, CHCl3) (Found: MH+ 344.1069. C17H18N3O3S
requires M 344.1069), IR (in CH2Cl2 solution) nmax/ cm-1: 3440 m,
1
3066 w, 2963 w, 2926 m, 2855 w, 1671 s, 1595 s and 1569 w. H
NMR (CDCl3, 400 MHz): d 1.57 (3H, d, J 6.6 Hz, CHOHCH3),
3.36 (3H, s, PhSCH3), 5.37 (1H, q, J 6.6 Hz, CHOHCH3) 7.39 to
7.75 (6H, m, 6-H, 7-H, 8-H (Q) and 3H (Ph)), 8.16 (1H, ddd, J
8.7 Hz, 1.4 Hz and 0.7 Hz, 5-H (Q)) and 8.33 (2H, dd, 8.4 Hz and
1.5 Hz, 2H (Ph)). 13C NMR (CDCl3, 100 MHz): d 20.9, 44.9, 66.1,
121.4, 126.8, 126.9, 127.4, 128.2, 129.6, 129.8, 134.3, 138.4, 145.9,
160.5 and 161.4).
Further elution with the same solvent mixture gave major
sulfoximine 20b diastereoisomer (Rf 0.12) as an oil (0.13 g, 37%).
[a]D -34.2 (c 0.5, CHCl3) (Found: MH+ 344.1068. C17H18N3O3S
requires M 344.1069), IR (in CH2Cl2 solution) nmax/ cm-1: 3456
Sulfoximination of phenyl c-hexyl sulfoxide using Q1NH2
General procedure 1 was followed using Q1NH2 1 (0.2 g,
1.1 mmol), LTA (0.52 g, 1.16 mmol), HMDS (0.34 g, 2.12 mmol)
and phenyl c-hexyl sulfoxide 16f (0.44 g, 2.12 mmol) in a solution
in dichloromethane (6 cm3). The crude product crystallised on
addition of ethanol to give sulfoximine 17f as a colourless solid
(0.29 g, 70%) mp 161–163 ◦C (from ethanol) IR (in CH2Cl2
solution) nmax/ cm-1: 3480 w, 3064 w, 3031 w, 2981 w, 2936 w,
1
w, 2964 m, 2928 m, 1739 s, 1671 s, 1597 s and 1569 w. H NMR
1
2874 w, 1672 s, 1608 w, 1592 s and 1568 w. H NMR (CDCl3,
(CDCl3, 400 MHz): d 1.52 (3H, d, J 6.6 Hz, CHOHCH3), 3.32
(3H, s, PhSCH3), 5.38 (1H, q, J 6.6 Hz, CHOHCH3) 7.43 to 7.76
(6H, m, 6-H, 7-H, 8-H (Q) and 3H (Ph)), 8.24 (1H, dd, J 8.1
Hz and 1.1 Hz, 5-H (Q)) and 8.33 (2H, dd, 8.8 Hz and 1.5 Hz,
2H (Ph)). 13C NMR (CDCl3, 100 MHz): d 21.8, 44.3, 65.6, 121.5,
400 MHz): d 1.07–1.91 (9H, m, 9H(c-Hex)),1.35 (3H, t, J 7.3 Hz,
QCH2CH3), 2.42 (1H, dd, J 12.4 and 6.9 Hz, 1H (c-Hex)), 3.17
(2H, m, QCH2CH3), 3.59 (1H, m, SCH), 7.28–7.65 (6H, m, 6-
H, 7-H, 8-H (Q) and 3H (Ph)), 8.08 (3H, m, 2H (Ph)) and 5-H
7892 | Org. Biomol. Chem., 2011, 9, 7887–7896
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126.8, 127.1, 127.3, 128.4, 129.8, 134.4, 134.5, 137.3, 145.9, 161.7
and 161.8).
and phenyl t-butyl sulfoxide 16d (1.06 g, 5.85 mmol) in a solution
in dichloromethane (10 cm3) to give sulfoximine 23 as a colourless
solid. The crude product contained a 1 : 1 ratio of sulfoximine
diastereoisomers from comparison of signals at d 5.44 and 5.53 in
its NMR spectrum (see below). The crude product was then chro-
matographed using chromatotron chromatography eluting with
hexane–ethyl acetate 2 : 1 gave one sulfoximine diastereoisomer
23a (Rf 0.3). The product crystallised on addition of ethanol to give
as a colourless solid (0.83 g, 34%) mp 156–157 ◦C (from ethanol).
[a]D = +61.347 (c = 0.47, CHCl3) IR (in CH2Cl2 solution) nmax/
cm-1: 3431 w, 3066 w, 2957 m, 2925 s, 2870 m, 2851 m, 1680 s,
Sulfoximination of phenyl ethyl sulfoxide using Q2NH2
General procedure 1 was followed using Q2NH2 18 (2.2 g,
11.7 mmol), LTA (6.21 g, 14.03 mmol), HMDS (3.77 g,
23.37 mmol) and phenyl ethyl sulfoxide 16b (3.6 g, 23.37 mmol)
in a solution in dichloromethane (20 cm3) to give sulfoximine
21 as a colourless oil. The crude product contained a 1 : 1 ratio
of sulfoximine diastereoisomers from comparison of signals at d
1.53 and 1.60 in its NMR spectrum (see below). The crude product
was then chromatographed over silica and eluting with hexane–
ethyl acetate 2 : 1 gave one sulfoximine diastereoisomer 21a (Rf
0.2) as a colourless oil (1.59 g, 38%). [a]D -33.5 (c 0.67, CHCl3)
(Found: MH+ 358.1224. C18H20N3O3S requires M 358.1225), IR
(in CH2Cl2 solution) nmax/ cm-1: 3436 m, 3065 w, 2978 m, 2933 m,
1
1594 s and1570m. H NMR (CDCl3, 400 MHz): d 1.52 (9H, s,
C(CH3)3), 1.61 (3H, d, J 6.23 Hz, CHOHCH3), 4.57 (1H, d, J
6.96 Hz, CHOHCH3), 5.53 (1H, m, CHOHCH3), 7.28–7.65 (6H,
m, 6-H, 7-H, 8-H (Q) and 3H (Ph)) and 8.01–8.12 (3H, m, 5-H
(Q)) and 2H (Ph)). 13C NMR (CDCl3, 100 MHz): d 22.1, 24.5,
63.5, 65.5, 121.5, 126.4, 126.7, 127.0., 128.6, 131.5, 133.7, 133.9,
135.3, 145.4, 161.1 and 161.8. Elemental analysis calculated for
C20H23N3O3S: C, 62.32; H, 6.01; N, 10.90; S, 8.32%. Found: C,
62.95; H, 6.09; N, 11.07, S, 8.36%.
Further elution with the same solvent mixture gave other
sulfoximine diastereoisomer 23b (Rf 0.17). The product crystallised
on addition of ethanol to give as a colourless solid (0.83 g, 34%) mp
151–153 ◦C (from ethanol) [a]D = +67.476 (c = 0.48, CHCl3) IR (in
CHCl3 solution) nmax/ cm-1: 3444 w, 3066 w, 2956 m, 2925 s, 2870
m, 2851 m, 1671 s, 1595 s and1569 w. 1H NMR (CDCl3, 400 MHz):
d 1.51 (9H, s, C(CH3)3), 1.64 (3H, d, J 6.6 Hz, CHOHCH3), 4.44
(1H, d, J 6.9 Hz CHOHCH3), 5.44 (1H, m, J 6.6 Hz, CHOHCH3),
7.30–7.66 (6H, m, 6-H, 7-H, 8-H (Q), 3H (Ph)), 7.90 (2H, d,
J 7.3 Hz, 2H (Ph)) and 8.04 (1H, d, J 8.1 Hz, 5-H (Q)). 13C
NMR (CDCl3, 100 MHz): d 22.1, 24.8, 64.7, 65.9, 121.1, 126.5,
126.9, 127.1, 127.0, 130.0, 133.4, 133.9, 135.6, 145.5, 159.8 and
160.3. Elemental analysis calculated for C20H23N3O3S: C, 62.32;
H, 6.01; N, 10.90; S, 8.32%. Found: C, 62.86, H, 5.86, N, 11.12, S,
8.38%.
1
1675 s, 1595 s and 1569 w. H NMR (CDCl3, 400 MHz): d 1.19
(3H, t, J 7.3 Hz, CH2CH3), 1.53 (3H, d, J 6.6 Hz, CHOHCH3),
3.51 (2H, m, CH2CH3), 5.39 (1H, q, J 6.6 Hz, CHOHCH3) 7.41
to 7.74 (6H, m, 6-H, 7-H, 8-H (Q) and 3H (Ph)), 8.18 to 8.23
(3H, m, 5-H (Q)) and 2H (Ph)). 13C NMR (CDCl3, 100 MHz):
d 8.3, 21.8, 50.7, 65.6, 121.3, 126.8, 127.0, 127.2, 129.0, 129.6,
134.3, 134.4, 135.3, 145.8, 161.5 and 161.9). Further elution with
the same solvent mixture gave other sulfoximine diastereoisomer
21b (Rf 0.1) as an oil (1.56 g, 37%). [a]D -57.4 (c 0.42, CHCl3)
1
(Found: MH+ 358.1225. C18H20N3O3S requires M 358.1225), H
NMR (CDCl3, 400 MHz): d 1.31 (3H, t, J 7.3 Hz, CH2CH3), 1.60
(3H, d, J 6.6 Hz, CHOHCH3), 3.57 (2H, m, CH2CH3), 4.45 (1H,
b, CHOHCH3), 5.41 (1H, b, CHOHCH3) 7.35 to 7.69 (6H, m,
6-H, 7-H, 8-H (Q) and 3H (Ph)), 8.11 (3H, d, 6.9 Hz, 5-H (Q)) and
2H (Ph)). 13C NMR (CDCl3, 100 MHz): d 7.6, 21.2, 51.0, 65.9,
121.4, 126.7, 126.9, 127.2, 128.8, 129.4, 134.0, 134.2, 137.2, 145.8,
160.8 and 161.4).
Sulfoximination of phenyl isopropyl sulfoxide using Q2NH2
General procedure 1 was followed using Q2NH2 18 (0.5 g,
2.44 mmol), LTA (1.19 g, 2.68 mmol), HMDS (0.79 g, 4.88 mmol)
and phenyl isopropyl sulfoxide 16c (0.82 g, 4.88 mmol) in a solu-
tion in dichloromethane (10 cm3) to give sulfoximine 22. The crude
product contained a 1 : 1 ratio of sulfoximine diastereoisomers
from comparison of signals at d 5.41 and 5.29 in its NMR spectrum
(see below). The crude product was then recrystallised on addition
of ethanol gave 1.4 : 1 diastereoisomeric mixture of sulfoximine 22
Sulfoximination of phenyl c-hexyl sulfoxide using Q2NH2
General procedure 1 was followed using Q2NH2 18 (0.5 g,
2.44 mmol), LTA (1.19 g, 2.68 mmol), HMDS (0.79 g, 4.88 mmol)
and phenyl c-hexyl sulfoxide 16f (1.02 g, 4.88 mmol) in a solution
in dichloromethane (10 cm3) to give sulfoximine 25. The crude
product contained a 1 : 1 ratio of sulfoximine diastereoisomers
from comparison of signals at d 5.34 and 5.45 in its NMR spec-
trum. Attempted chromatographic separation was unsuccessful.
The crude product was then recrystallised on addition of ethanol
to give a 95% diastereoisomeric excess of sulfoximine 25a as a
colourless solid (0.7 g, 70%) mp 169–170 ◦C (from ethanol). [a]D =
+71.25 (c = 0.4, CHCl3). IR (in CHCl3 solution) nmax/ cm-1: 3431 w,
3065 w, 2926 s, 2855 s, 1670 s, 1594 s and1569m. 1H NMR (CDCl3,
400 MHz): d 1.11–1.98 (10H, m, (CH2)5CHS), 1.59 (3H, d, J 6.2
Hz, CHOHCH3), 3.53 (1H, t, J 12.1 Hz, (CH2)5CHS), 4.51 (1H,
d, J 6.9 Hz, CHOHCH3), 5.45 (1H, p, J 6.2 Hz, CHOHCH3)
and 7.29–8.03 (9H, m, 5-H, 6-H, 7-H, 8-H (Q) and 5H (Ph)).
13C NMR (CDCl3, 100 MHz): d 21.9, 25.2, 25.4, 25.5, 25.7, 25.9,
63.9, 65.6, 121.5, 126.4, 126.92, 126.97, 129.0, 129.8, 133.7, 134.0,
136.7, 145.6, 161.1 and 161.7. Elemental analysis calculated for
C22H25N3O3S: C, 64.21; H, 6.12; N, 10.21; S, 7.79%. Found: C,
64.71, H, 6.06, N, 10.30, S, 7.86%.
◦
as a colourless solid (0.61 g, 71%) mp 84–87 C (from ethanol).
IR (in CHCl3 solution) nmax/ cm-1: 3431 w, 3065 w, 2980 w, 2934
w, 1675 s, 1594 s and1569m. 1H NMR (CDCl3, 400 MHz): signals
belong to mixture of diastereoisomers observable at d 1.09–1.69
(18H, aliphatic protons), 3.82 (4H, m, J 6.96 Hz, CH(CH3)2), 4.41
(2H, b, CHOHCH3), 4.51 (2H, b, CHOHCH3), 5.29 (1H, m, J 6.6
Hz, CHOHCH3), 5.41 (1H, m, J 6.6 Hz, CHOHCH3), 7.29–8.14
(9H, m, 5-H, 6-H, 7-H, 8-H (Q) and 5H (Ph). Elemental analysis
calculated for C19H21N3O3S: C, 61.44; H, 5.70; N, 11.31;S, 8.63%.
Found: C, 60.96, H, 5.70, N, 11.23, S, 8.41%.
Sulfoximination of phenyl tert-butyl sulfoxide using Q2NH2
General procedure 1 was followed using Q2NH2 18 (0.6 g,
2.93 mmol), LTA (1.56 g, 2.93 mmol), HMDS (0.94 g, 5.85 mmol)
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Sulfoximination of diphenyl sulfoxide using Q4NH2
Sulfoximination of phenyl benzyl sulfoxide using Q2NH2
General procedure 1 was followed using Q2NH2 18 (0.6 g,
2.93 mmol), LTA (1.56 g, 3.51 mmol), HMDS (0.94 g, 5.85 mmol)
and phenyl benzyl sulfoxide 16e (1.26 g, 5.85 mmol) in a solution
in dichloromethane (10 cm3) to give sulfoximine 24. The crude
product contained a 1 : 1 ratio of sulfoximine diastereoisomers
from comparison of signals at d 5.35 and 5.12 in its NMR spectrum
(see below). The crude product was then chromatographed using
a chromatotron and eluting with hexane–ethyl acetate 2 : 1 gave
one sulfoximine diastereoisomer 24a (Rf 0.27). The product
crystallised on addition of ethanol to give a colourless solid (0.39
g, 32%) mp 146–148 ◦C (from ethanol). [a]D = +36.773 (c = 0.55,
CHCl3) IR (in CH2Cl2 solution) nmax/ cm-1: 3446 w, 3032 w, 3065 w,
2927 w, 1675 s, 1595 s and 1569m. 1H NMR (CDCl3, 400 MHz):
d 1.48 (3H, d, J 6.2 Hz, CHOHCH3), 4.37 (1H, d, J 5.9 Hz,
CHOHCH3), 4.71 (2H, s, SCH2Ph), 5.35 (1H, m, CHOHCH3),
7.13–7.95 (11H, m, 6-H, 7-H, 8-H (Q), 5H (Ph) and 3H(Bn)) and
8.27 (1H, d, J 8.1 Hz, 5-H (Q)). 13C NMR (CDCl3, 100 MHz):
d 21.8, 63.3, 65.7, 121.4, 126.9, 127.1, 127.3, 127.9, 128.7, 129.1,
129.2, 129.3, 131.3, 134.3, 134.4, 135.1, 145.9, 161.6 and 162.1.
Elemental analysis calculated for C23H21N3O3S: C, 65.85; H, 5.05;
N, 10.02; S, 7.64%. Found: C, 66.58; H, 5.11; N, 10.20, S, 7.88%.
Further elution with the same solvent mixture gave the other
sulfoximine diastereoisomer 24b (Rf 0.15). The product crystallised
on addition of ethanol to give as a colourless solid (0.39 g, 32%)
mp 201–203 ◦C (from ethanol). [a]D = +48.505 (c = 0.54, CHCl3)
IR (in CHCl3 solution) nmax/ cm-1: 3440 w, 3065 w, 3033 w, 2958
General procedure 1 was followed using Q4NH2 31 (2.1 g,
6.437 mmol), LTA (2.184 g, 7.725 mmol), HMDS (2.08 g,
19.5 mmol) and diphenyl sulfoxide 16g (2.36 g, 7.724 mmol) in
a solution in dichloromethane (25 cm3) to give sulfoximine 34.
The crude product was then crystallised on addition of ethanol
gave sulfoximine 34 as a colourless solid (1.98 g, 71%) mp 164–
166 ◦C (from ethanol). [a]D = +45.1 (c = 1.1, CHCl3), IR (in CHCl3
solution) nmax/ cm-1: 3430 w, 3064 w, 2961 w, 2929 w, 2870 w, 1681
1
s, 1529 s and 1569m. H NMR (CDCl3, 400 MHz): d 0.72 (3H,
d, J 6.9 Hz, CH3CH3CH), 1.07 (3H,d, J 6.9 Hz, CH3CH3CH),
2.65 (1H, m, CH3CH3CH), 4.17 (1H, b, CHCHOH), 5.28 (1H,
b, CHCHOH) and 7.71 (14H m., 5-H, 6-H, 7-H, 8-H (Q), 10H
(Ph)). 13C NMR (CDCl3, 100 MHz): d 14.8, 20.4, 30.7, 121.19,
126.5, 126.9, 128.4, 128.6, 129.1, 129.5, 133.2, 133.7, 133.9, 139.91,
139.93, 145.2, 159.6 and 160.7. Elemental analysis calculated for
C24H23N3O3S: C, 66.49; H, 5.35; N, 9.69; S, 7.40%. Found: C,
66.41; H, 5.31; N, 9.66, S, 7.43%.
Sulfoximination of diphenyl sulfoxide using Q3NH2
General procedure 1 was followed using Q3NH2 30 (300 mg,
1.215 mmol), LTA (656 mg, 1.458 mmol), HMDS (392 mg,
2.43 mmol) and diphenyl sulfoxide 16g (368 mg, 1.822 mmol)
in a solution in dichloromethane (6 cm3) to give sulfoximine
33. The crude product was then chromatographed using column
chromatography eluting with hexane–ethyl acetate 3 : 1 gave
sulfoximine 33 as a light yellow solid (412 mg, 71%) mp 66–
67 ◦C (from ethanol). [a]D = +64.0 (c = 1.5, CHCl3), IR (in CHCl3
solution) nmax/ cm-1: 3485 w, 3064 w, 2953 w, 2953 w, 2867 w, 1678
s, 1608 w, 1588 s and 1567m. 1H NMR (CDCl3, 400 MHz): d 1.04
(9 H, s, (CH3)3C), 3.66 (1 H, d, J 9.7 Hz, CCHOH), 5.46 (1 H, d,
J 9.7 Hz, CCHOH) and 7.20–8.34 (14 H, m, 5-H, 6-H, 7-H, 8-H
(Q), 10H (Ph)). 13C NMR (CDCl3, 100 MHz): d 26.3, 38.0, 74.9,
121.3, 126.5, 126.8, 127.1, 128.5, 128.9, 129.0, 129.6, 133.1, 133.7,
133.8, 139.4, 139.6, 145.3, 159.9 and 160.4.
1
w, 2927 w, 2870 w, 2246 w, 1670 s, 1595 s and 1569m. H NMR
(CDCl3, 400 MHz): d 1.49 (3H, d, J 6.2 Hz, CHOHCH3), 4.31
(1H, d, J 5.9 Hz, CHOHCH3), 4.74 (1H, d, J 13.9 SCHHPh),
4.79 (1H, d, J 13.9 SCHHPh), 5.12 (1H, m, CHOHCH3), 7.10
(1H, d, J 7.3 Hz, 2H(Bn)), 7.22–7.94 (11H, m, 6-H, 7-H, 8-H (Q),
5H (Ph) and 3H(Bn)) and 8.17 (1H, d, J 8.06 Hz, 5-H (Q)). 13C
NMR (CDCl3, 100 MHz): d 21.4, 63.7, 65.8, 121.4, 126.7, 127.0,
127.3, 127.4, 128.6, 128.8, 128.9, 129.2, 129.4, 131.5, 133.9, 134.2,
137.4, 145.9, 160.8 and 161.6. Elemental analysis calculated for
C23H21N3O3S: C, 65.85; H, 5.05; N, 10.02; S, 7.64%. Found: C,
66.29, H, 5.01, N, 10.10, S, 7.80%.
Sulfoximination of diphenyl sulfoxide using Q5NH2
General procedure 1 was followed using Q5NH2 32 (500 mg,
2.146 mmol), LTA (995 mg, 2.25 mmol), HMDS (604 mg,
3.744 mmol) and diphenyl sulfoxide 16g (567 mg, 2.81 mmol)
in a solution in dichloromethane (10 cm3) to give sulfoximine 35.
The crude product was then crystallised on addition of ethanol
gave sulfoximine 35 as a colourless solid (670 mg, 77%) mp 178–
180 ◦C (from ethanol). [a]D = +5.0 (c = 0.8, CHCl3), IR (in
CHCl3 solution) nmax/ cm-1: 3385 w, 3063 w, 2924 w, 1681 s, 1593
s and 1568m. (Found: MH+ 468.1374. C27H22N3O3S requires M
468.1382), 1H NMR (CDCl3, 400 MHz): d 5.21 (1H, d, J 6.2 Hz,
PhCHOH), 6.29 (1H, d, J 6.2 Hz, PhCHOH) and 7.60 (19H, m. 5-
H, 6-H, 7-H, 8-H (Q), 15H (Ph)). 13C NMR (CDCl3, 100 MHz): d
71.7, 121.3, 126.7, 127.1, 127.9, 128.1, 128.14, 128.2, 128.5, 129.1,
129.4, 133.0, 133.3, 134.1, 140.4, 140.6, 140.8, 145.3, 158.4 and
160.4.
Sulfoximination of diphenyl sulfoxide using Q2NH2
General procedure 1 was followed using Q2NH2 18 (2 g,
9.75 mmol), LTA (5.19 g, 11.71 mmol), HMDS (3.15 g, 19.5 mmol)
and diphenyl sulfoxide 16g (2.37 g, 11.71 mmol) in a solution in
dichloromethane (25 cm3) to give sulfoximine 26. The crude prod-
uct was then crystallised on addition of ethanol gave sulfoximine
26 as a colourless solid (3 g, 76%) mp 136–38 ◦C (from ethanol).
[a]D = +36.399 (c = 0.53, CHCl3), IR (in CHCl3 solution) nmax/
cm-1: 3438 w, 3065 w, 2956 w, 2928 w, 2247 w, 1670 s, 1595 s and
1
1569m. H NMR (CDCl3, 400 MHz): d 1.61 (3H, d, J 6.6 Hz,
CHOHCH3), 4.43 (1H, d, J 6.2 Hz, CHOHCH3), 5.51 (1H, t, J
6.2 CHOHCH3), 7.32–7.67 (9H, m, 6-H, 7-H, 8-H (Q) and 6H
(Ph)), 8.01–8.08 (3H, m, 5-H (Q)) and 2H (Ph) and 8.27 (2H, dd,
J 8.8 and 1.5 Hz, 2H (Ph)). 13C NMR (CDCl3, 100 MHz): d 21.9,
65.9, 121.4, 126.6, 127.0, 128.6, 128.8, 129.2, 129.6, 133.5, 133.9,
134.1, 139.2, 139.3, 145.5, 160.7 and 161.1. Elemental analysis
calculated for C22H19N3O3S: C, 65.17; H, 4.72; N, 10.36; S, 7.91%.
Found: C, 65.74, H, 4.80, N, 10.44, S, 7.93%.
Sulfoximination of phenyl isopropyl sulfoxide using Q4NH2
General procedure 1 was followed using Q4NH2 31 (500 mg,
2.146 mmol), LTA (1.14 g, 2.575 mmol), HMDS (693 mg,
7894 | Org. Biomol. Chem., 2011, 9, 7887–7896
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4.292 mmol) and phenyl tert-butyl sulfoxide 16d (586 mg,
3.218 mmol) in a solution in dichloromethane (10 cm3) to give
sulfoximine 37. The crude product contained a 1 : 1 ratio of sulfox-
imine diastereoisomers from comparison of signals at d 5.16 and
5.37 ppm in its NMR spectrum (see below). The crude product was
then chromatographed using column chromatography eluting with
hexane–ethyl acetate 4 : 1 gave one sulfoximine diastereoisomer
37a (Rf 0.28). The product crystallised on addition of ethanol
to give sulfoximine 37a as a colourless solid (298 mg, 34%) mp
141–143 ◦C (Decomposed) (from ethanol). [a]D = +65.0 (c = 0.55,
CHCl3), IR (in CHCl3 solution) nmax/ cm-1: 3419 w, 3065 w, 2962
for C23H30N3O3S: 64.46; H, 7.06; N, 9.80; S, 7.48%. Found: 64.15;
H, 7.17; N, 9.65, S, 7.73%.
Further elution with the same solvent mixture gave sulfoximine
36b diastereoisomer (Rf 0.22) as an oil (329 mg, 34%). [a]D
=
+215.6 (c = 1.22, CHCl3) IR (in CH2Cl2 solution) nmax/ cm-1: 3472
w, 3065 w, 2953 w, 2868 w, 1681 s, 1589 m and 1567m. (Found: MH+
428.2001. C23H30N3O3S requires M 428.2008), 1H NMR (CDCl3,
400 MHz): d 1.03 (9H, s, (CH3)3CCH)), 1.49 (9H, s, (CH3)3CS)),
3.63 (1H, b, (CH3)3CCHOH)), 5.33 (1H, b, (CH3)3CCHOH)) and
7.25–8.05 (9H, m, 5-H, 6-H, 7-H, 8-H (Q), 5H (Ph)). 13C NMR
(CDCl3, 100 MHz): d 25.0, 26.2, 37.7, 65.3, 74.6, 121.1, 126.5,
126.9, 127.1, 128.5, 129.3, 130.1, 133.6, 133.7, 145.1, 158.9 and
160.2.
1
w, 2930 w, 2871 w, 1686 s, 1608 w, 1591 s and 1570m. H NMR
(CDCl3, 400 MHz): d 0.69 (3H, d, J 6.9 Hz, CH3CH3CHCH), 1.19
(3H, d, J 6.9 Hz, CH3CH3CHCH), 1.53 (9H, s, (CH3)3C)), 2.68
(1H, dtd, J 13.7, 7.0, 6.9, 2.6 Hz, CH3CH3CHCH), 4.31 (1H, b,
CHCHOH), 5.38 (1H, b, CHCHOH) and 7.27–8.18 (9H, m, 5-H,
6-H, 7-H, 8-H (Q), 5H (Ph)). 13C NMR (CDCl3, 100 MHz): d 14.8,
20.4, 24.5, 30.6, 63.4, 72.7, 121.4, 126.3, 126.8, 126.9, 128.6, 131.5,
133.6, 133.8, 135.4, 145.0, 160.3 and 161.1. Elemental analysis
calculated for C22H27N3O3S: 63.90; H, 6.58; N, 10.16; S, 7.75%.
Found: C, 63.60; H, 6.41; N, 10.18, S, 7.47%.
General procedure 2 for the reaction of aldehydes with Et2Zn in the
presence of sulfoximine 34
Under argon atmosphere, to ligand 34 (20.4 mg, 0.0472 mmol)
in dry Et2O (0.5 ml) in a oven dried 10 ml round bottom
flask was added Et2Zn (1 ml, 1 M hexane solution) at room
temperature in one portion and the solution stirred for 45 min.
A solution of Ti(OPri)4 (34 mg, 0.12 mmol) in Et2O (0.5 ml)
was then syringed into the reaction flask and with stirring for
a further for 45 min. The reaction mixture was then cooled to
-40 ◦C. After 5 min., freshly distilled aldehyde (0.472 mmol)
solution in Et2O (0.5 ml) was added and the reaction mixture
was stirred for 24 h at -40 ◦C. The reaction mixture was quenched
with saturated ammonium chloride and extracted with CH2Cl2.
The organic phase was dried with anhydrous Na2SO4, filtered
and concentrated. The enantiomeric purity of the product was
determined by GC. The absolute configurations of the products
were assigned by comparison with literature values.
Further elution with the same solvent mixture gave sulfoximine
37b diastereoisomer (Rf 0.2) as a colourless solid (298 mg, 34%).
mp 152–153 ◦C (Decomposed) (from ethanol). [a]D = +233.6 (c =
0.47, CHCl3) IR (in CH2Cl2 solution) nmax/ cm-1: 3430 w, 3065
1
w, 2964 w, 2930 w, 2871 w, 1681 s, 1592 s and 1569m. H NMR
(CDCl3, 400 MHz): d 0.74 (3H, d, J 6.8 Hz, CH3CH3CHCH),
1.14 (3H, d, J 6.8 Hz, CH3CH3CHCH), 1.51 (9H, s, (CH3)3C)),
2.64 (1H, dtd, J 14.0, 7.1, 6.8, 2.7 Hz, CH3CH3CHCH), 4.25 (1H,
b, CHCHOH), 5.16 (1 H, b, CHCHOH), 7.29–7.84 (8H, m, 6-
H, 7-H, 8-H (Q), 5H (Ph)) and 8.06 (1H, d, J 7.87 Hz, 5-H(Q)).
13C NMR (CDCl3, 100 MHz): d 14.8, 20.6, 25.0, 30.9, 65.1, 73.1,
120.8, 126.5, 126.7, 127.1, 129.2, 129.5, 133.2, 133.8, 135.5, 144.9,
158.1 and 160.0. Elemental analysis calculated for C22H27N3O3S:
C, 63.90; H, 6.58; N, 10.16; S, 7.75%. Found: 63.85; H, 6.57; N,
9.80, S, 7.53%.
Acknowledgements
We acknowledge to Dr R. S. Atkinson for his proofreading of this
manuscript. We are grateful to State Planning Organisation for
the financial support of this project and we also wish to thank
to Dr Graham Eaton at the Department of Chemistry of the
University of Leicester for the HRMS measurements of some of
our sulfoximines and Dr Ebru Mete for elemental analyses at the
Department of Chemistry of Ataturk University.
Sulfoximination of phenyl tert-butyl sulfoxide using Q3NH2
General procedure 1 was followed using Q3NH2 30 (500 mg,
2.025 mmol), LTA (1.8 g, 3.036 mmol), HMDS (653 mg,
4.05 mmol) and phenyl tert-butyl sulfoxide 16d (552 mg,
3.036 mmol) in a solution in dichloromethane (10 cm3) to give
sulfoximine 36. The crude product contained a 1 : 1 ratio of sulfox-
imine diastereoisomers from comparison of signals at d 5.33 and
5.50 ppm in its NMR spectrum (see below). The crude product was
then chromatographed using column chromatography eluting with
hexane–ethyl acetate 4 : 1 gave one sulfoximine diastereoisomer
36a (Rf 0.3). The product crystallised on addition of ethanol to give
as a colourless solid (329 mg, 34%) mp 133–135 ◦C (from ethanol).
[a]D = +39.7 (c = 0.42, CHCl3), IR (in CH2Cl2 solution) nmax/ cm-1:
3482 w, 3065 w, 2972 w, 2868 w, 1682 s, 1608 w, 1587 m and 1567m.
1H NMR (CDCl3, 400 MHz): d 1.06 (9H, s, (CH3)3CCH)), 1.56
(9H, s, (CH3)3CS)), 3.65 (1H, d, J 8.7 Hz, (CH3)3CCHOH)), 5.50
(1H, d, J 6.95 Hz, (CH3)3CCHOH)) and 7.27–8.19 (9H, m, 5-H,
6-H, 7-H, 8-H (Q), 5H (Ph)). 13C NMR (CDCl3, 100 MHz): d
24.6, 26.2, 38.1, 63.3, 74.4, 121.7, 126.2, 126.8, 127.0, 128.5, 131.8,
133.7, 134.9, 145.2, 160.8 and 160.9. Elemental analysis calculated
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